Dietary Restriction: Getting More From Your Mitochondria

Juvenon Health Journal volume 9 number 2 february 2010

By Benjamin V. Treadwell, Ph.D.

Cutting down caloric intake, or dietary restriction (DR), seems to produce benefits – i.e., a healthier, longer life – that are almost too good to be true. In the last issue of the Juvenon Health Journal (Volume 9, 1/10), I touched on a recent study that connected a balance of the essential amino acids (EAAs) to these positive effects. This month, let’s continue with a closer look at the cellular mechanisms involved and how they relate to DR benefits.

Shifting Cellular Functions
DR seems to promote a shift from nonessential cellular functions, such as cell growth/proliferation or the synthesis of fats and certain proteins, in favor of functions necessary to convert excess fat and blood sugar into more energy.

“DR’s net effect is an increase in proteins required to manufacture energy”

Protein synthesis, itself, is a good example. Although, in general, it declines by about 30% under DR, the translation of the messenger RNAs (mRNAs) coding for proteins that comprise the mitochondrial respiratory complex (proteins utilizing oxygen to produce energy) increases. In other words, the net effect is a decrease in non-mitochondrial proteins/enzymes and an increase in those proteins required to manufacture energy.

This is consistent with experimental results reported by numerous investigators. They show that the mitochondria are more active and churn out more ATP (adenosine triphosphate, the cell-useable form of energy) in DR animals, as compared to normally fed controls.

This effect also helps to explain the correlation between DR and improved cardiovascular health. The enzymes involved in fat synthesis, including cholesterol and triglycerides, are inhibited, whereas those proteins involved in producing active mitochondria, to support a more active organism, are up-regulated.

Why More Mitochondrial Proteins?
The answer was provided by work performed in the laboratories of the California Institute of Technology (Pasadena) and the Buck Institute for Age Research (Novato, CA). The researchers noted that an animal’s energy is produced by two metabolic pathways, one less efficient than the other. They theorized that, when food is scarce, the most efficient pathway for energy production will be utilized.

“there is a shift from anaerobic to aerobic metabolism with DR”

This is exactly what appears to happen with DR and the conversion of food metabolites to energy. There is a shift from anaerobic (glycolysis, non-oxygen requiring, less energy-efficient), to aerobic metabolism (Krebs cycle, oxygen-requiring, highly energy-efficient, occurring in the specific cell compartment, the mitochondrion). However, for this shift to occur, an increase in mitochondrial number and efficiency is necessary, as these are the cellular organelles where oxygen is utilized for the combustion of food and its conversion to ATP.

It turns out that the templates (RNA), containing the blueprints for the necessary mitochondrial protein constituents, have a unique structure that allows them to be more efficiently translated into proteins than the templates carrying the blueprints for non-mitochondrial proteins needed for fat synthesis and cell growth. (There are other important proteins with templates containing this unique structure, which are also synthesized, and they, too, are involved in protecting our cells from the stress imposed by nutrient deprivation.)

Cellular Signals
Other studies, attempting to determine the genes switched on by DR, have produced conflicting results. The reason for these contradictions appears to be that the earliest cellular response to DR is not at the gene level, but rather at the level of translation of specific m-RNAs.

The m-RNAs carrying the genetic code for proteins required for key metabolic events involved in energy production (mitochondrial proteins, etc.) contain a specific signal predisposing their translation into proteins in preference to those coding for less life-sustaining functions. This signal is built into the structure of one end (designated the 5 prime end) of the m-RNA and determines whether it will be recognized by the cell’s translational machinery, and translated into a protein.

“Evolution has produced an incredible smart and resilient cell”

DR also seems to affect the concentrations of signaling molecules, which activate or deactivate certain cellular machinery. For example, an increase in the flow of calcium into a cellular compartment activates AMPK (adenonsine monophosphate kinase), increasing fatty acid oxidation and deactivating mTOR (mammalian target of Rapamycin), associated with cell growth, as well as the cellular machinery involved in the production of fat.

One of the consequences of mTOR inhibition is more energy for cellular health-promoting activities. High caloric intake, on the other hand, activates insulin secretion and the insulin pathway, producing the opposite effect.

Health Results
So, millions of years of evolution have produced an incredibly smart and resilient cell to cope with unfavorable (low food availability) environmental conditions. But what does this all mean in terms of an animal’s response to disease?

Cancer is a prime example. DR animals appear to develop cancer at a significantly lower rate than animals fed an excess-calorie, diet. This may be related to at least two of the effects DR has on the cell.

First, cancer cells use much more glucose for energy than their normal counterparts, thriving on what’s produced by the less-efficient pathway, glycolysis. DR promotes energy production via the electron transport chain in the mitochondria (Krebs cycle), and away from the anaerobic glycolysis pathway.

“DR animals appear to develop cancer at a significantly lower rate”

Second, DR inhibits growth factor production. Growth factors are critical to the normal development of an organism, including humans. However, in post-developmental years (once the organism is physically mature), increased growth production in a tissue or organ can be detrimental to the health of the organism. Cancer seems to have the capacity to “hijack” the regulatory mechanisms for growth factor production to promote its own growth and metastasis.

DR Without CR
As I mentioned in last month’s Health Journal, DR requires reducing daily caloric intake by 30-40%. For most people, including scientists, this level of caloric restriction (CR) is probably not a reasonable expectation. Consequently, there is significant research directed toward the discovery of compounds capable of simulating DR-induced health benefits. Call me the eternal optimist, but I believe DR mimetics will be in our not-too-distant future.

A research team, from the California Institute of Technology and the Buck Institute for Age Research, recently continued the study of the effects of dietary restriction (DR) in a fruit fly model. They reported their results in Cellmagazine, with an article entitled, “4E-BP Extends Lifespan upon Dietary Restriction by Enhancing Mitochondrial Activity inDrosophila.”

Aware of previous work that noted a significant increase of mitochondrial energy production in both cells and animals with extended lifespans on a calorie-restricted diet, the investigators set out to identify the mechanism(s) involved. They initially determined that imposing DR decreased the synthesis of certain proteins by over 30%.

After a thorough examination of the protein synthesis translation complexes (polysomes) from the DR flies, however, they found that synthesis was actually inhibited for most proteins, except those comprising the respiratory complexes of the mitochondria. These proteins, which are required for energy production resulting in increased mitochondrial activity, were synthesized at a greater rate in the DR flies as compared to their normally fed counterparts.

Further examination led the team to discover that a particular property of the mRNAs coding for the respiratory proteins was involved. Generally, protein synthesis begins at one end of the mRNA, known as the 5 prime end, which is where a limiting initiation factor (eIF4E) binds and begins the process. However, a regulatory protein, 4E-BP, if present, binds to this initiation factor and inactivates it (forms an eIF4E-4E-BP complex).

In contrast, the mRNAs carrying the genetic information for proteins of the mitochondrial respiratory complex are not affected by the inactivation of eIF4E and, consequently, are translated. Why the translation differential?

The investigators observed that the mRNAs coding for the non-mitochondrial proteins contain a complex structure at their 5 prime ends, which increases their dependence on binding of eIF4E for translation. So with less active eIF4E available during dietary restriction, there is less translation of these mRNAs.

The mRNAs coding for the mitochondrial respiratory proteins, on the other hand, are not as sensitive to this inhibition, resulting in enhanced translation. These results seem to imply that translational regulation under DR plays an important role in maintaining mitochondrial activity and extending lifespan.

Read summary here.

This Research Update column highlights articles related to recent scientific inquiry into the process of human aging. It is not intended to promote any specific ingredient, regimen, or use and should not be construed as evidence of the safety, effectiveness, or intended uses of the Juvenon product. The Juvenon label should be consulted for intended uses and appropriate directions for use of the product.

Dr.Treadwell answers your questions.

question: I have been on Juvenon for several months. Within the first few weeks, I noticed that my memory was much better. For that reason alone, I will stay on Juvenon for the rest of my life.  I no longer tell people that I have a “bad” memory. Would you explain to me how and why this is happening? – thank you, 

answer: Thank you for your feedback, J. The active ingredients in Juvenon have been reported by many to have positive effects on memory. Why? Here’s the short answer.

The brain requires an enormous amount of energy to function efficiently and, in fact, this organ requires more energy than any other (except perhaps the muscular system during vigorous exercise). Memory formation involves numerous biochemical pathways in different areas of the brain (cortex, hypothalamus) before the process is complete.

The energy required to run the machinery (enzymes involved in the biochemical pathways) is all obtained from the mitochondria, those tiny cellular compartments where energy is produced. The nutrients in Juvenon support the health of the mitochondria and, thus, keep them running smoothly so as to produce the energy required for memory formation.

Benjamin V. Treadwell, Ph.D., is a former Harvard Medical School associate professor.